Many adverse side reactions of antitumor drugs resemble responses to bacterial endotoxin. We have demonstrated that many antitumor agents given in combination with a sublethal dose of bacterial lipopolysaccharide can cause an increased rate and extent of death in challenged BALB/c and DUB/ICR mice. The time of administration of drug with respect to bacterial endotoxin is determinative. Conceivably some of the adverse reactions seen in cancer patients undergoing chemotherapy may reflect this type of toxic synergy. Moreover, these studies may provide insight into means to improve the therapeutic efficacy of selected antitumor agents. Our first goal will be to determine the physiological bases of selected toxic synergies. Daunorubicin in combination with bacterial endotoxin in the mouse will be used as one model system for measuring effects on clearance and detoxification of the administered agents. Vincristine in combination with bacterial endotoxin in the mouse will be used as another model system. Our second goal is to assess the role of the normal flora (e.g., Bacteroides and Pseudomonas) and of bacterial components (e.g., complexes of lipid A and fatty acids with proteins) in precipitating adverse reactions to antitumor drugs. Our third goal will be to discover means for preventing these harmful interactions. Bibliographic references: S.G. Bradley and J.S. Bond (1975) Toxicity, clearance and metabolic effects of pactamycin in combination with bacterial lipopolysaccharide Toxicol. Appl. Pharmacol. 31: 208- 221. S.G. Bradly, A. C. Adams and M.C. Smith (1975) Potentiation of the toxicity of mithramycin by bacterial lipopolysaccharide. Antimicrobial Agt. Chemother. 7: 322-327.